Throughout this application, various references are referred to within parentheses. Disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains.
The designation xe2x80x9cxcex11axe2x80x9d is the appellation recently approved by the IUPHAR Nomenclature Committee for the previously designated xe2x80x9cxcex11cxe2x80x9d cloned subtype as outlined in the Pharmacological Reviews (Hieble, et al. (1995) Pharmacological Reviews 47: 267-270). The designation xcex11a is used throughout this application and the supporting tables and figures to refer to this receptor subtype. At the same time, the receptor formerly designated xcex11a was renamed xcex11d. The new nomenclature is used throughout this application. Stable cell lines expressing these receptors are described herein; however, these cell lines were deposited with the American Type Culture Collection (ATCC) under the old nomenclature (infra).
Benign Prostatic Hyperplasia (BPH), also called Benign Prostatic Hypertrophy, is a progressive condition which is characterized by a nodular enlargement of prostatic tissue resulting in obstruction of the urethra. This results in increased frequency of urination, nocturia, a poor urine stream, and hesitancy or delay in starting the urine flow. Chronic consequences of BPH can include hypertrophy of bladder smooth muscle, a decompensated bladder, and an increased incidence of urinary tract infection. The specific biochemical, histological, and pharmacological properties of the prostate adenoma leading to the bladder outlet obstruction are not yet known. However, the development of BPH is considered to be an inescapable phenomenon for the aging male population. BPH is observed in approximately 70% of males over the age of 70. Currently, in the United States, the method of choice for treating BPH is surgery (Lepor, H., Urol. Clinics North Amer., 17: 651, 1990). Over 400,000 prostatectomies are performed annually (data from 1986). The limitations of surgery for treating BPH include the morbidity rate of an operative procedure in elderly men, persistence or recurrence of obstructive and irritative symptoms, as well as the significant cost of surgery. A medicinal alternative to surgery is clearly very desirable.
xcex1-Adrenergic receptors (McGrath et al., Med. Res. Rev. 9: 407-533, 1989) are specific neuroreceptor proteins located in the peripheral and central nervous systems on tissues and organs throughout the body. These receptors are important switches for controlling many physiological functions and, thus, represent important targets for drug development. In fact, many xcex1-adrenergic drugs have been developed over the past 40 years. Examples include clonidine, phenoxybenzamine and prazosin (for treatment of hypertension), naphazoline (a nasal decongestant), and apraclonidine (for treatment of glaucoma). xcex1-adrenergic drugs can be broken down into two distinct classes: agonists (e.g., clonidine and naphazoline), which mimic the receptor activation properties of the endogenous neurotransmitter norepinephrine, and antagonists (e.g., phenoxybenzamine and prazosin), which act to block the effects of norepinephrine. Many of these drugs are effective, but also produce unwanted side effects (e.g., clonidine produces dry mouth and sedation in addition to its antihypertensive effects).
During the past 15 years, a more precise understanding of xcex1-adrenergic receptors and their drugs has evolved through increased scientific scrutiny. Prior to 1977, only one xcex1-adrenergic receptor was known to exist. Between 1977 and 1988, it was accepted by the scientific community that at least two xcex1-adrenergic receptors, xcex11 and xcex12, existed in the central and peripheral nervous systems. Since 1988, new techniques in molecular biology have led to the identification of at least six xcex1-adrenergic receptors which exist throughout the central and peripheral nervous systems: xcex11a (new nomenclature), xcex11b, xcex11d (new nomenclature), xcex12a, xcex12b and xcex12c (Bylund, D. B., FASEB J. 6: 832, 1992). In many cases, it is not known precisely which physiological responses in the body are controlled by each of these receptors. In addition, current xcex1-adrenergic drugs are not selective for any particular xcex1-adrenergic receptor. Many of these drugs produce untoward side effects that may be attributed to their poor xcex1-adrenergic receptor selectivity.
Since the mid 1970""s, nonselective xcex1-antagonists have been prescribed to treat BPH. In 1976, M. Caine et al. (Brit. J. Urol. 48: 255, 1976) reported that the nonselective xcex1-antagonist phenoxybenzamine was useful in relieving the symptoms of BPH. This drug may produce its effects by interacting with xcex1-receptors located on the prostate. However, this drug also produces significant side effects such as dizziness and asthenia, which severely limit its use in treating patients on a chronic basis. More recently, the xcex1-adrenergic antagonists prazosin and terazosin have also been found to be useful for treating BPH. However, these drugs also produce untoward side effects. It has recently been discovered that the xcex11a receptor is responsible for mediating the contraction of human prostate smooth muscle (Gluchowski, C. et al., WO 94/10989, 1994; Forray, C. et al., Mol. Pharmacol. 45: 703, 1994). This discovery indicates that the xcex11a antagonists may be effective agents for the treatment of BPH with decreased side effects. Further studies have indicated that the xcex11a receptor may also be present in other lower urinary tract tissues, such as urethral smooth muscle (Ford et al., Br. J. Pharmacol. 114: 24P, 1995).
This invention is directed to morpholinone and morpholine derivatives which are selective antagonists for cloned human xcex11a receptors. This invention is also related to uses of these compounds for lowering intraocular pressure (Zhan, et al., Ophthalmol. Vis. Sci. 34: Abst. #1133, 928, 1993), inhibiting cholesterol synthesis (D""Eletto and Javitt, J. Cardiovascular Pharmacol. 13: (Suppl. 2) S1-S4, 1989), benign prostatic hyperplasia, impotency (Milne and Wyllie, EP 0 459 666 A2, 1991), sympathetically mediated pain (Campbell, WO 92/14453, 1992), cardiac arrhythmia (Spiers, et al., J. Cardiovascular Pharmacol. 16: 824-830, 1990), migraine (K. A. Vatz, Headache 37: 107-108, 1997) and for the treatment of any disease where antagonism of the xcex11a receptor may be useful.
This invention is directed to a compound having the structure: 
where W is O, S, or NR8; wherein R8 is independently H, straight chained or branched C1-C7 alkyl, straight chained or branched C2-C7 alkenyl or alkynyl, C3-C7 cycloalkyl, or C5-C7 cycloalkenyl;
where Y is independently O or S;
where R2 is aryl or heteroaryl; wherein the aryl or heteroaryl may be substituted with one or more of F; Cl; Br; I; xe2x80x94CN; xe2x80x94NO2; xe2x80x94N(R8)2; xe2x80x94SO2R8; xe2x80x94(CH2)nC(Y)R8; xe2x80x94(CH2)nYR8; xe2x80x94(CH2)nC(Y)N(R8)2; xe2x80x94(CH2)nCO2R8; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl; or C5-C7 cycloalkenyl; and wherein n independently is an integer from 0 to 7 inclusive;
where R3 is independently H; straight chained or branched C1-C7 alkyl, monofluoroalkyl, or polyfluoroalkyl;
where R4 is H, xe2x80x94(CH2)tYR8, xe2x80x94(CH2)tC(Y)N(R8)2, xe2x80x94(CH2)tC(Y)R8, xe2x80x94(CH2)tCO2R8, xe2x80x94(CH2)tN(R8)2, xe2x80x94(CH2)tCN, xe2x80x94C(Y)R8, xe2x80x94C(Y)N(R8)2, xe2x80x94CO2R8, straight chained or branched C1-C7 alkyl, straight chained or branched C2-C7 alkenyl or alkynyl, C3-C7 cycloalkyl, C5-C7 cycloalkenyl, or phenyl or benzyl; wherein the phenyl or benzyl may be substituted with one or more of F; Cl; Br; I; xe2x80x94CN; xe2x80x94NO2; xe2x80x94N(R8)2; xe2x80x94SO2R8; xe2x80x94(CH2)nC(Y)R8; xe2x80x94(CH2)nYR8; xe2x80x94(CH2)nC(Y)N(R8)2; xe2x80x94(CH2)nCO2R8; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl; or C5-C7 cycloalkenyl; and wherein t independently is an integer from 1 to 4 inclusive;
where R5 is H, xe2x80x94(CH2)tYR8, xe2x80x94(CH2)tC(Y)N(R8)2, xe2x80x94(CH2)tC(Y)R8, xe2x80x94(CH2)tCO2R8, xe2x80x94(CH2)tN(R8)2, xe2x80x94(CH2)tCN, straight chained or branched C1-C7 alkyl, straight chained or branched C2-C7 alkenyl or alkynyl, C3-C7 cycloalkyl, C5-C7 cycloalkenyl, or phenyl or benzyl; wherein the phenyl or benzyl may be substituted with one or more of F; Cl; Br; I; xe2x80x94CN; xe2x80x94NO2; xe2x80x94N(R8)2; xe2x80x94SO2R8; xe2x80x94(CH2)nC(Y)R8; xe2x80x94(CH2)nYR8; xe2x80x94(CH2)nC(Y)N(R8)2; xe2x80x94(CH2)nCO2R8; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl; or C5-C7 cycloalkenyl;
where R6 is H, xe2x80x94(CH2)tYR8, xe2x80x94(CH2)tC(Y)N(R8)2, xe2x80x94(CH2)tC(Y)R8, xe2x80x94(CH2)tCO2R8, xe2x80x94(CH2)tN(R8)2, xe2x80x94(CH2)tCN, xe2x80x94C(Y)R8, xe2x80x94C(Y)N(R8)2, xe2x80x94CO2R8, straight chained or branched C1-C7 alkyl, straight chained or branched C2-C7 alkenyl or alkynyl, C3-C7 cycloalkyl, C5-C7 cycloalkenyl, or phenyl or benzyl; wherein the phenyl or benzyl may be substituted with one or more of F; Cl; Br; I; xe2x80x94CN; xe2x80x94NO2; xe2x80x94N(R8)2; xe2x80x94SO2R8; xe2x80x94(CH2)nC(Y)R8; xe2x80x94(CH2)nYR8; xe2x80x94(CH2)nC(Y)N(R8)2; xe2x80x94(CH2)nCO2R8; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl; or C5-C7 cycloalkenyl;
where R7 is H, xe2x80x94(CH2)tYR8, xe2x80x94(CH2)tC(Y)N(R8)2, xe2x80x94(CH2)tC(Y)R8, xe2x80x94(CH2)tCO2R8, xe2x80x94(CH2)tN(R8)2, xe2x80x94(CH2)tCN, straight chained or branched C1-C7 alkyl, straight chained or branched C2-C7 alkenyl or alkynyl, C3-C7 cycloalkyl, C5-C7 cycloalkenyl, or phenyl or benzyl; wherein the phenyl or benzyl may be substituted with one or more of F; Cl; Br; I; xe2x80x94CN; xe2x80x94NO2; xe2x80x94N(R8)2; xe2x80x94SO2R8; xe2x80x94(CH2)nC(Y)R8; xe2x80x94(CH2)nYR8; xe2x80x94(CH2)nC(Y)N(R8)2; xe2x80x94(CH2)nCO2R8; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl; or C5-C7 cycloalkenyl;
where q is an integer from 0 to 4 inclusive;
where each R8, n, and t independently is as defined above;
where R1 is 
wherein each R9 is H; straight chained or branched C1-C7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl, or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, or polyfluorocycloalkyl; C5-C7 cycloalkenyl; or aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more of F; Cl; Br; I; xe2x80x94(CH2)nYR8; xe2x80x94(CH2)nC(Y)R8; xe2x80x94(CH2)nC(Y)N(R8)2; xe2x80x94(CH2)nCO2R8; xe2x80x94CN; xe2x80x94NO2; xe2x80x94N(R8) 2; xe2x80x94SO2R8; straight chained or branched C1-C7 alkyl, monofluoroalkyl, or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, or polyfluorocycloalkyl; or C5-C7 cycloalkenyl;
wherein each R10 is H; F; xe2x80x94OH; xe2x80x94(CH2)nC(Y)R8; xe2x80x94(CH2)nYR8; xe2x80x94(CH2)nC(Y)N(R8)2; xe2x80x94(CH2)nCO2R8; xe2x80x94CN; xe2x80x94NO2; xe2x80x94N(R8)2; aryl or heteroaryl; straight chained or branched C1-C7 alkyl, hydroxyalkyl, aminoalkyl, carboxamidoalkyl, alkoxyalkyl, monofluoroalkyl, or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, or polyfluorocycloalkyl; or C5-C7 cycloalkenyl; wherein the alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, carboxamidoalkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl may be substituted with one or more aryl or heteroaryl; wherein the aryl or heteroaryl may be substituted with one or more of F; Cl; Br; I; xe2x80x94(CH2)nYR8; xe2x80x94(CH2)nC(Y)R8; xe2x80x94(CH2)nC(Y)N(R8)2; xe2x80x94(CH2)nCO2R8; xe2x80x94CN; xe2x80x94NO2; xe2x80x94N(R8)2; xe2x80x94SO2R8; straight chained or branched C1-C7 alkyl, monofluoroalkyl, or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, or polyfluorocycloalkyl; or C5-C7 cycloalkenyl;
wherein each R11 is independently H, xe2x80x94(CH2)tYR8, xe2x80x94(CH2)tC(Y)N(R8)2, xe2x80x94(CH2)tC(Y)R8, xe2x80x94(CH2)tCO2R8, xe2x80x94(CH2)tN(R8)2, xe2x80x94(CH2)tCN, xe2x80x94C(Y)R8, xe2x80x94C(Y)N(R8)2, xe2x80x94CO2R8, straight chained or branched C1-C7 alkyl, straight chained or branched C2-C7 alkenyl or alkynyl, C3-C7 cycloalkyl, or C5-C7 cycloalkenyl;
wherein each R12 is independently H, xe2x80x94(CH2)tYR8, xe2x80x94(CH2)tC(Y)N(R8)2, xe2x80x94(CH2)tC(Y)R8, xe2x80x94(CH2)tCO2R8, xe2x80x94(CH2)tN(R8)2, xe2x80x94(CH2)tCN, straight chained or branched C1-C7 alkyl, straight chained or branched C2-C7 alkenyl or alkynyl, C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein R13 is H, C1-C7 alkyl, xe2x80x94C(O)R2, aryl, heteroaryl, C1-C7 alkyl substituted with one or two aryl, or C1-C7 alkyl substituted with one or two heteroaryl; wherein the aryl or heteroaryl may be substituted with one or more of F; Cl; Br; I; xe2x80x94CN; xe2x80x94NO2; xe2x80x94N(R8)2; xe2x80x94SO2R8; xe2x80x94(CH2)nC(Y)R8; xe2x80x94(CH2)nYR8; xe2x80x94(CH2)nC(Y)N(R8)2; xe2x80x94(CH2)nCO2R8; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 aminoalkyl, alkenyl, or alkynyl; C3-C7 cycloalkyl; or C5-C7 cycloalkenyl;
wherein R14 iS H, straight chained or branched C1-C7 akyl;
wherein Z is O, S, NR14, CO, CH2, 
wherein Y1, Y2, and Y3 independently are H; F; Cl; Br; I; xe2x80x94CN; xe2x80x94NO2; xe2x80x94N(R8)2; xe2x80x94SO2R8; xe2x80x94(CH2)nC(Y)R8; xe2x80x94(CH2)nYR8; xe2x80x94(CH2)nC(Y)N(R8)2; xe2x80x94(CH2)nCO2R8; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl; or C5-C7 cycloalkenyl;
wherein each m is independently 1 or 2;
wherein each p is independently an integer from 0 to 2 inclusive;
wherein J is 
xe2x80x83or C2-C7 alkenyl;
wherein each R15 is independently H, xe2x80x94(CH2)tYR8, xe2x80x94(CH2)tC(Y)N(R8)2, xe2x80x94(CH2)tC(Y)R8, xe2x80x94(CH2)tCO2R8, xe2x80x94(CH2)tN(R8)2, xe2x80x94(CH2)tCN, xe2x80x94C(Y)R8, xe2x80x94C(Y)N(R8)2, xe2x80x94CO2R8, straight chained or branched C1-C7 alkyl, straight chained or branched C2-C7 alkenyl or alkynyl, C3-C7 cycloalkyl, or C5-C7 cycloalkenyl;
wherein each R16 is independently H, xe2x80x94(CH2)tYR8, xe2x80x94(CH2)tC(Y)N(R8)2, xe2x80x94(CH2)tC(Y)R8, xe2x80x94(CH2)tCO2R8, xe2x80x94(CH2)tN(R8)2, xe2x80x94(CH2)tCN, straight chained or branched C1-C7 alkyl, straight chained or branched C2-C7 alkenyl or alkynyl, C3-C7 cycoalkyl, or C5-C7 cycloalkenyl;
wherein each R17 is independently H; F; xe2x80x94(CH2)tYR8; xe2x80x94(CH2)tC(Y)N(R8)2; xe2x80x94(CH2)tC(Y)R8; xe2x80x94(CH2)tCO2R8; xe2x80x94(CH2)tN(R8)2; xe2x80x94(CH2)tCN; xe2x80x94C(Y)R8; xe2x80x94C(Y)N(R8)2; xe2x80x94CO2R8; straight chained or branched Cl-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl; or C5-C7 cycloalkenyl;
wherein each R18 is independently H; F; xe2x80x94(CH2)tYR8; xe2x80x94(CH2)tC(Y)N(R8)2; xe2x80x94(CH2)tC(Y)R8; xe2x80x94(CH2)tCO2R8; xe2x80x94(CH2)tN(R8)2; xe2x80x94(CH2)tCN; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl; or C5-C7 cycloalkenyl;
wherein L is S, O, or N(R8);
wherein u is an integer from 0 to 1 inclusive;
or a pharmaceutically acceptable salt thereof.
This invention provides for a pharmaceutical composition comprising a therapeutically effective amount of any one of the compounds described herein and a pharmaceutically acceptable carrier.
This invention provides for a method of treating a subject suffering from benign prostatic hyperplasia which comprises administering to the subject an amount of any one of the compounds described herein effective to treat benign prostatic hyperplasia.
This invention provides for a method of treating a subject suffering from high intraocular pressure which comprises administering to the subject an amount of any one of the compounds described herein effective to lower intraocular pressure.
This invention provides for a method of treating a subject suffering from a disorder associated with high cholesterol which comprises administering to the subject an amount of any one of the compounds described herein effective to inhibit cholesterol synthesis.
This invention provides for a method of treating a subject suffering from cardiac arrhythmia which comprises administering to the subject an amount of any one of the compounds described herein effective to treat cardiac arrhythmia.
This invention provides for a method of treating a subject suffering from impotency which comprises administering to the subject an amount of any one of the compounds described herein effective to treat impotency.
This invention provides for a method of treating a subject suffering from sympathetically mediated pain which comprises administering to the subject an amount of any one of the compounds described herein effective to treat sympathetically mediated pain.
This invention provides for a method of treating a subject suffering from migraine which comprises administering to the subject an amount of any one of the compounds described herein effective to treat migraine.
This invention provides for a method of treating a disease which is susceptible to treatment by antagonism of the xcex11a receptor which comprises administering to the subject an amount of any one of the compounds described herein effective to treat the disease.
This invention provides for a method of treating a subject suffering from benign prostatic hyperplasia which comprises administering to the subject an amount of any one of the compounds described herein in combination with a 5-alpha reductase inhibitor effective to treat benign prostatic hyperplasia.
This invention provides for a pharmaceutical composition comprising a therapeutically effective amount of any one of the compounds described herein in combination with a therapeutically effective amount of finasteride and a pharmaceutically acceptable carrier.
This invention provides for a method of relaxing lower urinary tract tissue which comprises contacting the lower urinary tract tissue with an amount of any one of the compounds described herein effective to relax lower urinary tract tissue.
This invention provides for a method of relaxing lower urinary tract tissue in a subject which comprises administering to the subject an amount of any one of the compounds described herein effective to relax lower urinary tract tissue.
This invention provides for a pharmaceutical composition made by combining a therapeutically effective amount of any one of the compounds described herein and a pharmaceutically acceptable carrier.
This invention provides for a pharmaceutical composition made by combining a therapeutically effective amount of any one of the compounds described herein with a therapeutically effective amount of finasteride and a pharmaceutically acceptable carrier.
This invention provides for a process for making a pharmaceutical composition comprising combining a therapeutically effective amount of any one of the compounds described herein and a pharmaceutically acceptable carrier.
This invention provides for a process for making a pharmaceutical composition comprising combining a therapeutically effective amount of any one of the compounds described herein with a therapeutically effective amount of finasteride and a pharmaceutically acceptable carrier.